Kidney is an organ that filters waste products and excess water from blood to generate urine so as to maintain homeostasis of body fluid (extracellular fluid) and excrete protein metabolites such as urea. In addition, the kidney is responsible for regulation of endocrine secretion and metabolism such as vitamin D activation, erythropoietin production or renin production. Therefore, the kidney is known as a very important organ for the living body.
Examples of kidney diseases include acute glomerulonephritis, chronic glomerulonephritis, nephrotic syndrome, pyelonephritis, hypertensive nephrosclerosis, diabetic glomerulosclerosis, nephrolithiasis, amyloid nephropathy, renal vein thrombosis, Alport syndrome, and renal tumor. The kidney is an organ having a complex structure. In general, deterioration of renal function is irreversible except for some acute diseases. In addition, renal diseases progress as predicted, eventually resulting in “chronic renal failure.” As a result of symptomatic progression, dialysis becomes required. In the case of dialysis, patients must continuously receive dialysis for 4 to 6 hours a day two or three times per week through life. Therefore, the QOL of patients is remarkably impaired. At the same time, the medical cost required for dialysis is extremely expensive (¥1,300,000,000,000), causing an enormous burden on the total medical expense in Japan (¥33,000,000,000,000). This has been problematic.
To date, a variety of drug therapies have been performed for various renal diseases. For example, drug therapies for glomerulonephritis include administration of corticosteroids for suppression of inflammatory reaction and an immunosuppressive therapy. In addition, in the case of renal cell cancer that is a major kidney cancer, stent placement and a drug therapy using molecular target drugs such as Nexavar (Sorafenib) have been conducted, in addition to surgical resection. The term “renal cell cancer” used herein refers to adenocarcinoma formed through malignant alteration of renal tubular epithelial cells in the kidney. However, satisfactory drug treatment still has not been realized in clinical practice because such drug therapies are problematic in terms of levels of side effects upon non-kidney organs, efficacy, and the like.
Meanwhile, drug delivery systems (DDSs) that allow efficient distribution of drugs to target organs have been actively studied and developed for practical use in recent years. For instance, a method using drug-carrying vesicles such as liposomes, emulsions, lipid microspheres, and nanoparticles, improved stability of PEG-modified drugs or drug carriers in blood, active targeting with the use of antibodies, and the like are suggested.
However, there are various problems relating to the drug delivery system using these techniques. It has been difficult to achieve effective delivery of drugs to kidney lesions in particular. For example, when drug-carrying vesicles are used, drug-carrying vesicles are likely to be captured in the liver, spleen, or the like, making it difficult to achieve targeting of even a normal kidney. Further, it is very difficult to perform separate targeting of normal kidney tissue and affected kidney tissue.
In particular, it is known that very large amounts of drugs pass through the kidney because of the large blood flow volume of the kidney (0.8 to 1.2 liters/minute corresponding to 20% to 25% of the cardiac output for adults). However, in spite of such large amounts of drugs passing through the kidney, substantial amounts of drugs are not transferred to kidney functional units but are excreted in urine. Therefore, sufficient drug efficacy has not been exhibited in the kidney. In addition, substantially no drug carriers capable of delivering a drug targeting a kidney or kidney functional units have been available. There are a very small number of reports on effective drug carriers capable of aiding drug targeting. One example of such drug carriers is a polyvinylpyrrolidone compound (Nature Biotechnology 21, 399-404 (2003) Synthesis of a poly(vinylpyrrolidone-co-dimethyl maleic anhydride) co-polymer and its application for renal drug targeting). However, polyvinylpyrrolidone is known as a non-bioabsorbable material that can never be degraded or metabolized in vivo (JECFA Roma, 24 Mar.-2 Apr. 1980: Toxicological Evaluation of Certain Food Additives: WHO Food Additive Series No. 15). The above compound is designed to prevent filtration/excretion through the kidney. Therefore, in order to achieve drug accumulation in the kidney, a foreign substance which is a non-bioabsorbable material needs to remain in the kidney for long time. This is significantly problematic. For such reason, it is actually difficult to use the compound in practice. In particular, the long-term retention of the compound in the kidney would increase the risk of unexpected drug-induced nephrotoxic side effects. It is known that many drugs and contrast agents cause nephrotoxic side effects. Specifically, it is important for kidney-targeting carriers to be transferred to kidney functional units immediately after being administered while having transient accumulation effects. After administration, it is desirable for kidney-targeting carriers to be removed from the kidney in an adequate manner by degradation/metabolism/excretion. For example, it is desirable for contrast agents, PET diagnostic agents (radioisotope diagnostic agents) and the like to be accumulated in 1 or 2 hours after administration and is then removed as soon as possible. However, in the above case, it was found that the polyvinylpyrrolidone compound continuously remains in the kidney at high concentrations for several days or longer. It has been impossible to solve this issue. Further, it is impossible for the above polyvinylpyrrolidone compound to achieve separate targeting of normal kidney tissue and affected kidney tissue. Therefore, the long-term retention of the compound in a normal kidney would inevitably increase the risk of unexpected drug-induced nephrotoxic side effects. Therefore, it has been problematic that the compound cannot be used in practice as an agent targeting an affected kidney.
In addition, many imaging agents/in vivo diagnostic drugs have no selectivity to distinguish between a normal kidney and an affected kidney, which has been problematic. PET (positron emission tomography) diagnosis of legions with the use of FDG (fluorodeoxyglucose) has been employed for tumor or inflammation diagnosis. However, non-specific physiological accumulation of FDG results in accumulation of FDG in a normal kidney/urinary duct. This causes an increase in the background level, making it difficult to make a diagnosis of a legion formed in a kidney or urinary duct. Also for in vivo diagnostic drugs, imaging agents capable of separately targeting normal kidney tissue and affected kidney tissue have been awaited.
That is, a targeting agent that separately targets a normal kidney and an affected kidney while having transient accumulation effects has been strongly demanded as a kidney-imaging agent. Meanwhile, for example, in the case of IgA nephropathy diagnosis, there is a report on a composition comprising an anti-IgA antibody (JP Patent Publication (Kohyo) No. 2009-503115 A). However, this composition which is provided in this document is composed of an antibody. Therefore, such composition merely acts on limited diseases (e.g., only IgA nephropathy in the case of the anti-IgA antibody described in the document). Therefore, the composition obviously lacks versatility and thus it is also not useful in practice as a diagnostic agent. That is, a versatile targeting agent capable of targeting a kidney in which a wide range of diseases are developed has been awaited.
On the other hand, biopolymers such as gelatin have been widely used as medical materials. However, it has been unknown that biopolymers can be used for targeting of an affected kidney. In addition, along with the recent development of genetic engineering techniques, protein synthesis has been conducted via gene introduction into Escherichia coli or yeast. With the use of this technique, a variety of recombinant collagen-like proteins have been synthesized (e.g., U.S. Pat. No. 6,992,172; and WO2008/103041). Such proteins are superior to natural gelatin in terms of non-infectious properties and homogeneity. In addition, since the sequences of the proteins have been determined, the proteins are advantageous in that they can be precisely designed in terms of strength and degradability. However, the above suggestion is limited to the use of the proteins as a substitute of natural gelatin. Needless to say, it has been unknown that they can be used as targeting agents for an affected kidney.